The present invention relates to drug compositions for relieving pain and promoting the removal of calculi in urolithiasis. The drug compositions of this invention contain active ingredients having stimulating effects on both xcex22- and xcex23-adrenoceptors.
It is known that three subtypes of xcex2-adrenoceptor, which have been classified as xcex21, xcex22 and xcex23 are present in the human body. Each receptor subtype is distributed in specified organs. xcex21-Adrenoceptor is mainly present in the heart and its stimulation enhances the function of the heart. xcex22-Adrenoceptor is mainly present in the trachea, peripheral blood vessels and the uterus. Smooth muscle of such organs is relaxed by the stimulation of this receptor. In addition, it has recently been reported that xcex23-adrenoceptor is present in the digestive tract and adipocytes. The stimulation of xcex23-adrenoceptor leads to the relaxation of gastrointestinal smooth muscle, lipolysis and energy expenditure in adipose tissues and so on.
Thus, the distribution of xcex2-adrenoceptor subtypes is specified by organs and tissues. Various receptor subtypes including xcex2-adrenoceptor have been actively studied for developing more effective medicinal treatment of some diseases. Consequently, efforts have been paid extensively to develop more effective and highly selective drugs that act upon a specified organ. However, xcex2-adrenoceptor subtypes distributed in human ureter have not yet been elucidated, although the progress of studies to develop drugs that act more effectively on human ureter has been desired.
Urolithiasis is a disease generating calculi in the lumen of the entire urinary tract from kidney to urethra. The calculi is thought to be formed in a series of events such as nucleation of urinary component, crystallization, aggregation, concretion and enlargement. Urinary flow is often obstructed by calculi, which results in the rise of intra-ureteral pressure leading to pain. An analgesic and an antispastic are prescribed for the pain. However, the use of the analgesic is only temporary symptomatic therapy for the pain, and is not expected to fundamentally treat urolithiasis. The effectiveness of an anti-cholinergic, one of the antispastics, is also not satisfactory. Therefore, drugs which can relieve pain and promote the removal of calculi by widening the ureter due to strong relaxing effects are desired (The Journal of Urology, Vol. 152, pp. 1095-1098 (1994)).
The present inventors have extensively studied drug effects on the human ureter in order to elucidate the xcex2-adrenoceptor subtypes distributed therein. As a result, it has been surprisingly found that xcex23-adrenoceptor in addition to xcex22-adrenoceptor was present in human ureter, thereby forming the basis of the present invention.
Accordingly, the present invention is to provide novel drugs for relieving pain and for promoting the removal of calculi in urolithiasis. Useful drugs of this invention contain active ingredients which exert a strong relaxing effect on human ureteral smooth muscle by stimulating both xcex22- and xcex23-adrenoceptors.